Curcumin compositions and methods of use as an nk3 antagonist

ABSTRACT

Disclosed herein are compositions for treating, ameliorating, preventing, or reducing the symptoms associated with menopause and/or hot flashes. The compositions disclosed herein comprise a curcumin composition, a green tea extract composition, and a phycocyanin composition that act as neurokinin 3 receptor antagonists. Also described herein are methods utilizing the aforementioned compositions.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No.63/278,989 filed on Nov. 12, 2021, the disclosure of which isincorporated herein by reference in its entirety.

BACKGROUND

The neurokinin 3 (NK3) receptor is mainly expressed in the centralnervous system and is the most selective of the tachykinin receptors,with highly preferential binding and activation by its endogenous ligandneurokinin-B (NKB). Research on the NK3 receptor, compared to theneurokinin-1 (NKI) and neurokinin-2 (NK2) receptors, has received littleattention, in large part due to the absence of potent and selectivenon-peptide NK3 receptor antagonists. The inventors have identified agrowing demand to develop novel NK3 receptor antagonists, because theinventors have identified the relationship between the NK3 receptoragonists and menopausal symptoms, which include hot flashes and nightsweats. NK3 receptor antagonists are suspected to alleviate suchsymptoms. NK3 receptor antagonists are believed to confer many potentialbenefits to subjects, however the development of effective antagonistshas eluded scientists in the prior art. As such, there is a need todevelop and provide NK3 antagonists. By providing NK3 antagonists aspharmaceutical agents and/or dietary supplements, therapeutic andnutraceutical benefits can be realized, either individually,collectively, or in conjunction with other pharmaceutical agents and/ordietary supplements.

SUMMARY

Embodiments of the present disclosure relate to novel NK3 receptorantagonists and their use in the amelioration and/or treatment ofmenopause or symptoms associated therewith.

These and other features, aspects, and advantages of the presentembodiments will become understood with reference to the followingdescription, appended claims, and accompanying figures.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A shows the dose response curve of a curcumin composition, asdescribed herein, which was administered to transfected Chinese HamsterOvary (CHO) cells in vitro.

FIG. 1B shows the dose response curve of a green tea extractcomposition, as described herein, which was administered to transfectedChinese Hamster Ovary (CHO) cells in vitro.

FIG. 1C shows the dose response curve of a phycocyanin composition, asdescribed herein, which was administered to transfected Chinese HamsterOvary (CHO) cells in vitro.

FIG. 2 shows the results of administration of a curcumin composition, agreen tea extract composition, and a phycocyanin composition, and thecombination thereof administered to female Wistar rats in vivo. FIG. 2shows the hypothalamus levels of NKB for non-ovariectomized femaleWistar rats (C); ovariectomized female Wistar rats (OVX); ovariectomizedfemale Wistar rats treated with 600 mg human equivalent dose (HED) of acurcumin composition, as described herein (OVX+CL); ovariectomizedfemale Wistar rats treated with 300 mg HED of a green tea extractcomposition, as described herein (OVX+EGCG); ovariectomized femaleWistar rats treated with 100 mg HED of a phycocyanin composition, asdescribed herein (OVX+P); and ovariectomized female Wistar rats treatedwith the combination of a curcumin composition, a green tea extractcomposition, and a phycocyanin composition, as disclosed herein, at theaforementioned dosages (OVX+CL+EGCG+P). The densitometric analysis ofthe relative intensity according to the control group of the westernblot bands was performed with β-actin normalization to ensure equalprotein loading. Blots were repeated at least three times (n = 3) and arepresentative blot is shown. Data are presented as mean ± standarddeviation. Different lowercase letters above data series (a-d) indicatea statistical difference between groups.

FIG. 3 shows the results of administration of combinations of a curcumincomposition, a green tea extract composition, and a phycocyanincomposition, as described herein, to female Wistar rats in vivo, whereinthe dosages of the curcumin composition and green tea extractcomposition were varied. FIG. 3 shows the hypothalamus levels of NKB fora non-ovariectomized female Wistar rats (C); ovariectomized femaleWistar rats (OVX); combination-treated ovariectomized female Wistarrats, wherein the treatment was 600 mg HED of a curcumin composition,300 mg HED of a green tea extract composition, and 100 mg HED of aphycocyanin composition (OVX+CL1+EGCG1+P); combination-treatedovariectomized female Wistar rats, wherein the treatment was 450 mg HEDof a curcumin composition, 450 mg HED of a green tea extractcomposition, and 100 mg HED of a phycocyanin composition(OVX+CL2+EGCG2+-P); and combination-treated ovariectomized female Wistarrats, wherein the treatment was 720 mg HED of a curcumin composition,180 mg HED a green tea extract composition, and 100 mg HED of aphycocyanin composition (OVX+CL3+EGCG3+P). The densitometric analysis ofthe relative intensity according to the control group of the westernblot bands was performed with β-actin normalization to ensure equalprotein loading. Blots were repeated at least three times (n = 3) and arepresentative blot is shown. Data are presented as mean ± standarddeviation. Different lowercase letters above data series (a-f) indicatea statistical difference between groups.

DETAILED DESCRIPTION

Some embodiments provide a composition comprising an amount of one ormore curcumin extracts formulated as a curcumin composition. In certainembodiments, a curcumin composition can comprise an amount ofdiferuloylmethane, an amount of demethoxycurcumin (DMC), an amount ofbis-demethoxycurcumin (BDMC), an amount of tetrahydrocurcumin, an amountof dihydrocurcumin, an amount of hexahydrocurcumin, an amount ofoctahydrocurcumin, or a combination of any of the foregoing. In someembodiments, a curcumin composition, as described herein, may comprise apharmaceutically acceptable vehicle, carrier, or diluent.

Diferuloylmethane is depicted below:

DMC is depicted below:

BDMC is depicted below:

Tetrahydrocurcumin is depicted below:

Dihydrocurcumin is depicted as follows:

Hexahydrocurcumin is depicted as follows:

Octahydrocurcumin is depicted as follows:

In some embodiments, a curcumin composition, as described herein, maycomprise an amount of at least two of diferuloylmethane, DMC, BDMC,tetrahydrocurcumin, dihydrocurcumin, hexahydrocurcumin, andoctahydrocurcumin. For example, a curcumin composition can comprise anamount of diferuloylmethane and an amount of DMC present in a ratio ofabout 1:1, or about 20:1 to about 1:20 of diferuloylmethane to DMC, orany range therebetween. In some embodiments, a curcumin composition cancomprise an amount of diferuloylmethane and an amount of BDMC, presentin a ratio of about 1:1, or about 20:1 to about 1:20 ofdiferuloylmethane to BDMC, or any range therebetween. In certainembodiments, a curcumin composition can comprise an amount ofdiferuloylmethane and an amount of tetrahydrocurcumin present in a ratioof about 1:1, or about 20:1 to about 1:20 of diferuloylmethane totetrahydrocurcumin, or any range therebetween. In some embodiments, acurcumin composition can comprise an amount of diferuloylmethane and anamount of dihydrocurcumin present in a ratio of about 1:1, or about 20:1to about 1:20 of diferuloylmethane to dihydrocurcumin, or any rangetherebetween. In certain embodiments, a curcumin composition cancomprise an amount of diferuloylmethane and an amount ofhexahydrocurcumin present in a ratio of about 1:1, or about 20:1 toabout 1:20 of diferuloylmethane to hexahydrocurcumin, or any rangetherebetween. In some embodiments, a curcumin composition can comprisean amount of diferuloylmethane and an amount of octahydrocurcuminpresent in a ratio of about 1:1, or about 20:1 to about 1:20 ofdiferuloylmethane to octahydrocurcumin, or any range therebetween. Incertain embodiments, a curcumin composition can comprise an amount ofDMC and an amount of BDMC present in a ratio of about 1:1, or about 20:1to about 1:20 of DMC to BDMC, or any range therebetween. In someembodiments, a curcumin composition can comprise an amount of DMC and anamount of tetrahydrocurcumin present in a ratio of about 1:1, or about20:1 to about 1:20 of DMC to tetrahydrocurcumin, or any rangetherebetween. In certain embodiments, a curcumin composition cancomprise an amount of DMC and an amount of dihydrocurcumin present in aratio of about 1:1, or about 20:1 to about 1:20 of DMC todihydrocurcumin, or any range therebetween. In some embodiments, acurcumin composition can comprise an amount of DMC and an amount ofhexahydrocurcumin present in a ratio of about 1:1, or about 20:1 toabout 1:20 of DMC to hexahydrocurcumin, or any range therebetween. Incertain embodiments, a curcumin composition can comprise an amount ofDMC and an amount of octahydrocurcumin present in a ratio of about 1:1,or about 20:1 to about 1:20 of DMC to octahydrocurcumin, or any rangetherebetween. In some embodiments, a curcumin composition can comprisean amount of BDMC and an amount of tetrahydrocurcumin present in a ratioof about 1:1, or about 20:1 to about 1:20 of BDMC to tetrahydrocurcumin,or any range therebetween. In certain embodiments, a curcumincomposition can comprise an amount of BDMC and an amount ofdihydrocurcumin present in a ratio of about 1:1, or about 20:1 to about1:20 of BDMC to dihydrocurcumin, or any range therebetween. In someembodiments, a curcumin composition can comprise an amount of BDMC andan amount of hexahydrocurcumin present in a ratio of about 1:1, or about20:1 to about 1:20 of BDMC to hexahydrocurcumin, or any rangetherebetween. In certain embodiments, a curcumin composition cancomprise an amount of BDMC and an amount of octahydrocurcumin present ina ratio of about 1:1, or about 20:1 to about 1:20 of BDMC tooctahydrocurcumin, or any range therebetween. In certain embodiments, acurcumin composition can comprise an amount of tetrahydrocurcumin and anamount of dihydrocurcumin present in a ratio of about 1:1, or about 20:1to about 1:20 of tetrahydrocurcumin to dihydrocurcumin, or any rangetherebetween. In some embodiments, a curcumin composition can comprisean amount of tetrahydrocurcumin and an amount of hexahydrocurcuminpresent in a ratio of about 1:1, or about 20:1 to about 1:20 oftetrahydrocurcumin to hexahydrocurcumin, or any range therebetween. Incertain embodiments, a curcumin composition can comprise an amount oftetrahydrocurcumin and an amount of octahydrocurcumin present in a ratioof about 1:1, or about 20:1 to about 1:20 of tetrahydrocurcumin tooctahydrocurcumin, or any range therebetween. In some embodiments, acurcumin composition can comprise an amount of dihydrocurcumin and anamount of hexahydrocurcumin present in a ratio of about 1:1, or about20:1 to about 1:20 of dihydrocurcumin to hexahydrocurcumin, or any rangetherebetween. In certain embodiments, a curcumin composition cancomprise an amount of dihydrocurcumin and an amount of octahydrocurcuminpresent in a ratio of about 1:1, or about 20:1 to about 1:20 ofdihydrocurcumin to octahydrocurcumin, or any range therebetween. Incertain embodiments, a curcumin composition can comprise an amount ofhexahydrocurcumin and an amount of octahydrocurcumin present in a ratioof about 1:1, or about 20:1 to about 1:20 of hexahydrocurcumin tooctahydrocurcumin, or any range therebetween. As described furtherherein, any two of the aforementioned compounds can be present in aratio of about 20:1, about 10:1, about 9:1, about 8:1, about 7:1, about6:1, about 5:1, about 4:1, about 3:1, about 2:1, about 1:1, about 1:2,about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about1:9, about 1:10, about 1:20, or any ratio in between. In view of theresults and discussion contained herein, one of skill in the art wouldunderstand how to formulate a curcumin composition of the instantdisclosure to achieve the results described herein.

In certain embodiments, a curcumin composition, as described herein, maycomprise an amount of three or more of diferuloylmethane, DMC, BDMC,tetrahydrocurcumin, dihydrocurcumin, hexahydrocurcumin, andoctahydrocurcumin. The three or more compounds may be present in aratio. The ratio can be understood as comprising a “part” of anycompound. For example, a curcumin composition may comprise a ratio of4:1:10, diferuloylmethane to DMC to BDMC, corresponding to 4 partsdiferuloylmethane, 1 part DMC, and 10 parts BDMC. The individual amountof any of the aforementioned compounds may be as low as 1 part, may beas high as 20 parts, or may any value therebetween. In view of theresults and discussion contained herein, one of skill in the art wouldunderstand how to formulate a curcumin composition of the instantdisclosure to achieve the results described herein.

Some embodiments provide a composition comprising an amount of one ormore green tea extracts formulated as a green tea extract composition.In certain embodiments, a green tea extract composition can comprise anamount of epigallocatechin gallate (EGCG), an amount of epicatechin(EC), an amount of epigallocatechin (EGC), an amount of epicatechingallate (ECG), or a combination of any of the foregoing. In someembodiments, a green tea extract composition, as described herein, maycomprise a pharmaceutically acceptable vehicle, carrier, or diluent.

EGCG is depicted below:

EC is depicted below:

EGC is depicted below:

ECG is depicted below:

In some embodiments, a green tea extract composition, as describedherein, may comprise an amount of at least two of EGCG, EC, EGC, andECG. For example, a green tea extract composition can comprise an amountof EGCG and an amount of EC present in a ratio of about 1:1, or about20:1 to about 1:20 of EGCG to EC, or any range therebetween. In someembodiments, a green tea extract composition can comprise an amount ofEGCG and an amount of EGC present in a ratio of about 1:1, or about 20:1to about 1:20 of EGCG to EGC, or any range therebetween. In certainembodiments, a green tea extract composition can comprise an amount ofEGCG and an amount of ECG present in a ratio of about 1:1, or about 20:1to about 1:20 of EGCG to ECG, or any range therebetween. In someembodiments, a green tea extract composition can comprise an amount ofEC and an amount of EGC present in a ratio of about 1:1, or about 20:1to about 1:20 of EC to EGC, or any range therebetween. In certainembodiments, a green tea extract composition can comprise an amount ofEC and an amount of ECG present in a ratio of about 1:1, or about 20:1to about 1:20 of EC to ECG, or any range therebetween. In someembodiments, a green tea extract composition can comprise an amount ofEGC and an amount of ECG present in a ratio of about 1:1, or about 20:1to about 1:20 of EGC to ECG, or any range therebetween. As describedfurther herein, any two of the aforementioned compounds can be presentin a ratio of about 20:1, about 10:1, about 9:1, about 8:1, about 7:1,about 6:1, about 5:1, about 4:1, about 3:1, about 2:1, about 1:1, about1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8,about 1:9, about 1:10, about 1:20, or any ratio in between. In view ofthe results and discussion contained herein, one of skill in the artwould understand how to formulate a green tea extract composition of theinstant disclosure to achieve the results described herein.

In certain embodiments, a green tea extract composition, as describedherein, may comprise an amount of three or more of EGCG, EC, EGC, andECG. The three or more compounds may be present in a ratio. The ratiocan be understood as comprising a “part” of any compound. For example, agreen tea extract composition may comprise a ratio of 4:1:10, EGCG to ECto EGC, corresponding to 4 parts EGCG, 1 part EC, and 10 parts EGC. Theindividual amount of any of the aforementioned compounds may be as lowas 1 part, may be as high as 20 parts, or may any value therebetween. Inview of the results and discussion contained herein, one of skill in theart would understand how to formulate a green tea extract composition ofthe instant disclosure to achieve the results described herein.

Some embodiments provide a composition comprising an amount of one ormore phycocyanin-related compounds formulated as a phycocyanincomposition. As used herein, the term “phycocyanin-related compounds”refers to compounds that are pigment-proteins found in Spirulina, orcompounds derived therefrom either by extraction, enzymatic degradation,or other known methods in the art. Exemplary examples ofphycocyanin-related compounds include, but are not limited tophycocyanin, extracts of phycocyanin, phycocyanin peptides, andphycocyanin oligopeptides, and the like. In certain embodiments, aphycocyanin composition can comprise an amount of phycocyanin, an amountof an extract of phycocyanin, an amount of phycocyanin peptides, anamount of phycocyanin oligopeptides, or a combination of any of theforegoing. In some embodiments, a phycocyanin composition, as describedherein, may comprise a pharmaceutically acceptable vehicle, carrier, ordiluent.

In some embodiments, a phycocyanin composition, as described herein, maycomprise an amount of at least two of phycocyanin or an extract thereof,phycocyanin peptides, or phycocyanin oligopeptides. For example, aphycocyanin composition can comprise an amount of phycocyanin and anamount of an extract of phycocyanin present in a ratio of about 1:1, orabout 20:1 to about 1:20 of phycocyanin to an extract of phycocyanin, orany range therebetween. In some embodiments, a phycocyanin compositioncan comprise an amount of phycocyanin and an amount of phycocyaninpeptides present in a ratio of about 1:1, or about 20:1 to about 1:20 ofphycocyanin to phycocyanin peptides, or any range therebetween. Incertain embodiments, a green tea extract composition can comprise anamount of phycocyanin and an amount of phycocyanin oligopeptides presentin a ratio of about 1:1, or about 20:1 to about 1:20 of phycocyanin tophycocyanin oligopeptides, or any range therebetween. In someembodiments, a phycocyanin composition can comprise an amount of anextract of phycocyanin and an amount of phycocyanin peptides present ina ratio of about 1:1, or about 20:1 to about 1:20 of an extract ofphycocyanin to phycocyanin peptides, or any range therebetween. Incertain embodiments, a green tea extract composition can comprise anamount of an extract of phycocyanin and an amount of phycocyaninoligopeptides present in a ratio of about 1:1, or about 20:1 to about1:20 of an extract of phycocyanin to phycocyanin oligopeptides, or anyrange therebetween. In some embodiments, a green tea extract compositioncan comprise an amount of phycocyanin peptides and an amount ofphycocyanin oligopeptides present in a ratio of about 1:1, or about 20:1to about 1:20 of phycocyanin peptides to phycocyanin oligopeptides, orany range therebetween. As described further herein, any two of theaforementioned compounds can be present in a ratio of about 20:1, about10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1,about 3:1, about 2:1. about 1:1, about 1:2, about 1:3, about 1:4, about1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, about 1:20,or any ratio in between. In view of the results and discussion containedherein, one of skill in the art would understand how to formulate aphycocyanin composition of the instant disclosure to achieve the resultsdescribed herein.

In certain embodiments, a phycocyanin composition, as described herein,may comprise an amount of three or more of phycocyanin, an extract ofphycocyanin, phycocyanin peptides, and phycocyanin oligopeptides. Thethree or more compounds may be present in a ratio. The ratio can beunderstood as comprising a “part” of any compound. For example, aphycocyanin composition may comprise a ratio of 4:1:10, phycocyanin tophycocyanin peptides to phycocyanin oligopeptides, corresponding to 4parts phycocyanin, 1 part phycocyanin peptides, and 10 parts phycocyaninoligopeptides. The individual amount of any of the aforementionedcompounds may be as low as 1 part, may be as high as 20 parts, or mayany value therebetween. In view of the results and discussion containedherein, one of skill in the art would understand how to formulate aphycocyanin composition of the instant disclosure to achieve the resultsdescribed herein.

Some embodiments provide a composition comprising an amount of acurcumin composition, as described herein, an amount of a green teaextract composition, as described herein, an amount of a phycocyanincomposition, as described herein, or any combination of the foregoingformulated as a combination composition.

In some embodiments, a combination composition, as described herein, maycomprise an amount of at least two of a curcumin composition, asdescribed herein, a green tea extract composition, as described herein,and a phycocyanin composition, as described herein. For example, acombination composition can comprise an amount of a curcumincomposition, as described herein, and an amount of a green tea extractcomposition, as described herein, present in a ratio of about 1:1, orabout 20:1 to about 1:20 of a curcumin composition, as described herein,to a green tea extract composition, as described herein, or any rangetherebetween. In some embodiments, a combination composition cancomprise an amount of a curcumin composition, as described herein, andan amount of a phycocyanin composition, as described herein, present ina ratio of about 1:1, or about 20:1 to about 1:20 of a curcumincomposition, as described herein, to a phycocyanin composition, asdescribed herein, or any range therebetween. In certain embodiments, acombination composition can comprise an amount of a green tea extractcomposition, as described herein, and an amount of a phycocyanincomposition, as described herein, present in a ratio of about 1:1, orabout 20:1 to about 1:20 of a green tea extract composition, asdescribed herein, to a phycocyanin composition, as described herein, orany range therebetween. As described further herein, any two of theaforementioned compositions comprising a combination composition can bepresent in a ratio of about 20:1, about 10:1, about 9:1, about 8:1,about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, about 2:1, about1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7,about 1:8, about 1:9, about 1:10, about 1:20, or any ratio in between.In view of the results and discussion contained herein, one of skill inthe art would understand how to formulate a combination composition ofthe instant disclosure to achieve the results described herein.

In certain embodiments, a combination composition, as described herein,may comprise an amount of a curcumin composition, as described herein,an amount of a green tea extract composition, as described herein, andan amount of a phycocyanin composition, as described herein, provided asa ratio, The ratio of curcumin composition to green tea extractcomposition to phycocyanin may be provided in a ratio of about 1:1:1,1:1:2, 1:1:3, 1:1:4, 1:1:5, 1:1:6, 1:1:7, 1:1:8, 1:1:9, 1:1:10, 1:2:1,1:2:2, 1:2:3, 1:2:4, 1:2:5,1:2:6,1:2:7,1:2:8,1:2:9,1:2-10,1:3:1,1:3:2.1:3:3, , , , , , , 1:2:6, , ,, , , 1:3:4, 1:3:5, 1:3:6, 1:3:7, 1:3:8, 1:3:9, 1:3:10, 1:4:1, 1:4:2,1:4:3, 1:4:4, 1:4:5, 1:4:6, 1:4:7, 1:4:8, 1:4:9, 1:4:10, 1:5:1, 1:5:2,1:5:3, 1:5:4, 1:5:5, 1:5:6, 1:5:7,1:5:8,1:5:9,1:5:10,1:6:1,1:6:2,1:6:3,1:6:4, 1:6:5, 1:6:6, 1:6:7, 1:6:8, 1:6:9, 1:6:10, 1:7:1, 1:7:2, 1:7:3,1:7:4, 1:7:5, 1:7:6, 1:7:7, 1:7:8, 1:7:9, 1:7:10, 1:8:1, 1:8:2, 1:8:3,1:8:4, 1:8:5, 1:8:6, 1:8:7, 1:8:8, 1:8:9, 1:8:10, 1:9:1, 1:9:2, 1:9:3,1:9:4, 1:9:5, 1:9:6, 1:9:7, 1:9:8, 1:9:9, 1:9:10, 1:10:1, 1:10:2,1:10:3, 1:10:4, 1:10:5, 1:10:6, 1:10:7, 1:10:8, 1:10:9, 1:10:10, 2:1:1,2:1:2, 2:1:3, 2:1:4, 2:1:5, 2:1:6, 2:1:7, 2:1:8, 2:1:9, 2:1:10, 2:2:1,2:2:2, 2:2:3, 2:2:4, 2:2:5, 2:2:6, 2:2:7, 2:2:8, 2:2:9, 2:2:10, 2:3:1,2:3:2, 2:3:3, 2:3:4, 2:3:5, 2:3:6,2:3:7,2:3:8,2:3:9,2:3:10,2:4:1,2:4:2,2:4:3,2:4:4,2:4:5,2:4:6,2:4:7,2:4:8,2:4:9,2:4:10,2:5:1,2:5:2, 2:5:3, 2:5:4, 2:5:5, 2:5:6, 2:5:7, 2:5:8, 2:5:9, 2:5:10, 2:6:1,2:6:2, 2:6:3, 2:6:4, 2:6:5, 2:6:6,2:6:7,2:6:8,2:6:9,2:6:10,2:7:1,2:7:2,2:7:3,2:7:4,2:7:5,2:7:6,2:7:7,2:7:8,2:7:9,2:7:10,2:8:1,2:8:2, 2:8:3, 2:8:4, 2:8:5, 2:8:6, 2:8:7, 2:8:8, 2:8:9, 2:8:10, 2:9:1,2:9:2, 2:9:3, 2:9:4, 2:9:5, 2:9:6, 2:9:7, 2:9:8, 2:9:9, 2:9:10, 2:10:1,2:10:2, 2:10:3, 2:10:4, 2:10:5, 2:10:6, 2:10:7, 2:10:8, 2:10:9,2:10:10,3:1:1,3:1:2,3:1:3,3:1:4,3:1:5,3:1:6,3:1:7,3:1:8,3:1:9,3:1:10,3:2:1,3:2:2,3:2:3,3:2:4,3:2:5, 3:2:6, 3:2:7, 3:2:8, 3:2:9, 3:2:10, 3:3:1, 3:3:2, 3:3:3, 3:3:4,3:3:5, 3:3:6, 3:3:7, 3:3:8, 3:3:9, 3:3:10, 3:4:1, 3:4:2, 3:4:3,3:4:4,3:4:5, 3:4:6,3:4:7, 3:4:8, 3:4:9,3:4:10, 3:5:1,3:5:2,3:5:3, 3:5:4,3:5:5, 3:5:6, 3:5:7, 3:5:8, 3:5:9, 3:5:10, 3:6:1, 3:6:2, 3:6:3, 3:6:4,3:6:5, 3:6:6, 3:6:7, 3:6:8, 3:6:9, 3:6:10,3:7:1,3:7:2,3:7:3,3:7:4,3:7:5, 3:7:6,3:7:7, 3:7:8, 3:7:9, 3:7:10, 3:8:1,3:8:2,3:8:3, 3:8:4, 3:8:5, 3:8:6, 3:8:7, 3:8:8, 3:8:9, 3:8:10, 3:9:1,3:9:2, 3:9:3, 3:9:4, 3:9:5, 3:9:6, 3:9:7, 3:9:8, 3:9:9, 3:9:10, 3:10:1,3:10:2, 3:10:3, 3:10:4, 3:10:5,3:10:6, 3:10:7, 3:10:8,3:10:9,3:10:10,4:1:1,4:1:2, 4:1:3, 4:1:4, 4:1:5, 4:1:6, 4:1:7, 4:1:8, 4:1:9,4:1:10, 4:2:1, 4:2:2, 4:2:3, 4:2:4, 4:2:5, 4:2:6, 4:2:7, 4:2:8, 4:2:9,4:2:10, 4:3:1, 4:3:2, 4:3:3, 4:3:4, 4:3:5, 4:3:6, 4:3:7, 4:3:8, 4:3:9,4:3:10, 4:4:1, 4:4:2, 4:4:3,4:4:4,4:4:5, 4:4:6, 4:4:7,4:4:8,4:4:9,4:4:10,4:5:1, 4:5:2, 4:5:3,4:5:4,4:5:5, 4:5:6, 4:5:7, 4:5:8, 4:5:9,4:5:10, 4:6:1, 4:6:2, 4:6:3, 4:6:4, 4:6:5, 4:6:6, 4:6:7, 4:6:8, 4:6:9,4:6:10, 4:7:1. 4:7:2, 4:7:3,4:7:4, 4:7:5, 4:7:6, 4:7:7,4:7:8,4:7:9,4:7:10, 4:8:1, 4:8:2, 4:8:3,4:8:4,4:8:5, 4:8:6, 4:8:7, 4:8:8, 4:8:9,4:8:10, 4:9:1, 4:9:2, 4:9:3, 4:9:4, 4:9:5, 4:9:6, 4:9:7, 4:9:8, 4:9:9,4:9:10, 4:10:1, 4:10:2, 4:10:3, 4:10:4, 4:10:5, 4:10:6, 4:10:7, 4:10:8,4:10:9, 4:10:10, 5:1:1, 5:1:2, 5:1:3, 5:1:4, 5:1:5, 5:1:6, 5:1:7, 5:1:8,5:1:9, 5:1:10, 5:2:1, 5:2:2, 5:2:3, 5:2:4, 5:2:5, 5:2:6, 5:2:7, 5:2:8,5:2:9, 5:2:10, 5:3:1, 5:3:2, 5:3:3, 5:3:4, 5:3:5, 5:3:6, 5:3:7, 5:3:8,5:3:9, 5:3:10, 5:4:1, 5:4:2,5:4:3, 5:4:4, 5:4:5, 5:4:6, 5:4:7, 5:4:8,5:4:9, 5:4:10, 5:5:1, 5:5:2, 5:5:3, 5:5:4, 5:5:5, 5:5:6, 5:5:7, 5:5:8,5:5:9, 5:5:10, 5:6:1, 5:6:2, 5:6:3, 5:6:4,5:6:5, 5:6:6,5:6:7, 5:6:8,5:6:9, 5:6:10, 5:7:1, 5:7:2,5:7:3, 5:7:4, 5:7:5, 5:7:6, 5:7:7, 5:7:8,5:7:9, 5:7:10, 5:8:1, 5:8:2, 5:8:3, 5:8:4, 5:8:5, 5:8:6, 5:8:7, 5:8:8,5:8:9, 5:8:10, 5:9:1, 5:9:2, 5:9:3, 5:9:4, 5:9:5, 5:9:6, 5:9:7, 5:9:8,5:9:9, 5:9:10, 5:10:1, 5:10:2, 5:10:3,5:10:4,5:10:5,5:10:6,5:10:7,5:10:8,5:10:9,5:10:10,6:1:1,6:1:2,6:1:3,6:1:4,6:1:5,6:1:6,6:1:7,6:1:8, 6:1:9, 6:1:10, 6:2:1, 6:2:2, 6:2:3, 6:2:4, 6:2:5, 6:2:6, 6:2:7,6:2:8, 6:2:9, 6:2:10, 6:3:1, 6:3:2, 6:3:3, 6:3:4, 6:3:5, 6:3:6, 6:3:7,6:3:8, 6:3:9, 6:3:10, 6:4:1, 6:4:2, 6:4:3, 6:4:4, 6:4:5, 6:4:6, 6:4:7,6:4:8,6:4:9,6:4:10,6:5:1,6:5:2,6:5:3, 6:5:4, 6:5:5, 6:5:6,6:5:7,6:5:8,6:5:9,6:5:10,6:6:1,6:6:2, 6:6:3, 6:6:4, 6:6:5, 6:6:6, 6:6:7,6:6:8, 6:6:9, 6:6:10, 6:7:1, 6:7:2, 6:7:3, 6:7:4, 6:7:5, 6:7:6, 6:7:7,6:7:8, 6:7:9, 6:7:10, 6:8:1, 6:8:2, 6:8:3, 6:8:4, 6:8:5, 6:8:6, 6:8:7,6:8:8, 6:8:9, 6:8:10, 6:9:1, 6:9:2,6:9:3,6:9:4,6:9:5,6:9:6,6:9:7,6:9:8,6:9:9,6:9:10,6:10:1,6:10:2,6:10:3,6:10:4,6:10:5,6:10:6,6:10:7, 6:10:8, 6:10:9, 6:10:10, 7:1:1, 7:1:2, 7:1:3, 7:1:4, 7:1:5,7:1:6, 7:1:7, 7:1:8, 7:1:9, 7:1:10, 7:2:1, 7:2:2, 7:2:3, 7:2:4, 7:2:5,7:2:6, 7:2:7, 7:2:8, 7:2:9, 7:2:10, 7:3:1, 7:3:2, 7:3:3, 7:3:4, 7:3:5,7:3:6, 7:3:7, 7:3:8, 7:3:9, 7:3:10, 7:4:1, 7:4:2, 7:4:3, 7:4:4, 7:4:5,7:4:6,7:4:7, 7:4:8,7:4:9, 7:4:10, 7:5:1, 7:5:2, 7:5:3, 7:5:4, 7:5:5,7:5:6, 7:5:7, 7:5:8, 7:5:9, 7:5:10, 7:6:1, 7:6:2, 7:6:3, 7:6:4, 7:6:5,7:6:6, 7:6:7, 7:6:8, 7:6:9, 7:6:10, 7:7:1, 7:7:2, 7:7:3, 7:7:4, 7:7:5,7:7:6, 7:7:7, 7:7:8, 7:7:9, 7:7:10, 7:8:1, 7:8:2, 7:8:3, 7:8:4, 7:8:5,7:8:6, 7:8:7, 7:8:8, 7:8:9, 7:8:10, 7:9:1, 7:9:2, 7:9:3, 7:9:4, 7:9:5,7:9:6, 7:9:7, 7:9:8, 7:9:9, 7:9:10, 7:10:1, 7:10:2, 7:10:3, 7:10:4,7:10:5, 7:10:6, 7:10:7, 7:10:8, 7:10:9, 7:10:10, 8:1:1, 8:1:2, 8:1:3,8:1:4, 8:1:5, 8:1:6, 8:1:7, 8:1:8, 8:1:9, 8:1:10, 8:2:1, 8:2:2, 8:2:3,8:2:4, 8:2:5, 8:2:6, 8:2:7, 8:2:8, 8:2:9, 8:2:10, 8:3:1, 8:3:2, 8:3:3,8:3:4, 8:3:5, 8:3:6, 8:3:7, 8:3:8,8:3:9, 8:3:10, 8:4:1, 8:4:2, 8:4:3,8:4:4, 8:4:5, 8:4:6, 8:4:7, 8:4:8, 8:4:9, 8:4:10, 8:5:1, 8:5:2, 8:5:3,8:5:4, 8:5:5, 8:5:6, 8:5:7, 8:5:8, 8:5:9, 8:5:10, 8:6:1, 8:6:2, 8:6:3,8:6:4, 8:6:5, 8:6:6, 8:6:7, 8:6:8, 8:6:9, 8:6:10, 8:7:1, 8:7:2, 8:7:3,8:7:4, 8:7:5, 8:7:6, 8:7:7, 8:7:8, 8:7:9, 8:7:10, 8:8:1, 8:8:2, 8:8:3,8:8:4, 8:8:5, 8:8:6, 8:8:7, 8:8:8, 8:8:9, 8:8:10, 8:9:1, 8:9:2, 8:9:3,8:9:4, 8:9:5, 8:9:6, 8:9:7, 8:9:8, 8:9:9, 8:9:10, 8:10:1, 8:10:2,8:10:3, 8:10:4, 8:10:5, 8:10:6, 8:10:7, 8:10:8, 8:10:9, 8:10:10, 9:1:1,9:1:2, 9:1:3, 9:1:4, 9:1:5, 9:1:6, 9:1:7, 9:1:8, 9:1:9, 9:1:10, 9:2:1,9:2:2, 9:2:3, 9:2:4, 9:2:5, 9:2:6, 9:2:7, 9:2:8, 9:2:9, 9:2:10, 9:3:1,9:3:2, 9:3:3, 9:3:4, 9:3:5, 9:3:6, 9:3:7, 9:3:8, 9:3:9, 9:3: 10, 9:4:1,9:4:2, 9:4:3, 9:4:4, 9:4:5, 9:4:6, 9:4:7, 9:4:8, 9:4:9, 9:4:10, 9:5:1,9:5:2, 9:5:3, 9:5:4, 9:5:5, 9:5:6, 9:5:7, 9:5:8, 9:5:9, 9:5:10, 9:6:1,9:6:2, 9:6:3, 9:6:4, 9:6:5, 9:6:6, 9:6:7, 9:6:8, 9:6:9, 9:6:10, 9:7:1,9:7:2, 9:7:3, 9:7:4, 9:7:5, 9:7:6, 9:7:7, 9:7:8, 9:7:9, 9:7:10, 9:8:1,9:8:2, 9:8:3, 9:8:4, 9:8:5, 9:8:6,9:8:7,9:8:8,9:8:9, 9:8:10, 9:9:1,9:9:2, 9:9:3, 9:9:4, 9:9:5, 9:9:6,9:9:7, 9:9:8,9:9:9, 9:9:10, 9:10:1,9:10:2, 9:10:3, 9:10:4, 9:10:5, 9:10:6, 9:10:7, 9:10:8, 9:10:9, 9:10:10,10:1:1, 10:1:2, 10:1:3, 10:1:4, 10:1:5, 10:1:6, 10:1:7, 10:1:8, 10:1:9,10:1:10, 10:2:1, 10:2:2, 10:2:3, 10:2:4, 10:2:5, 10:2:6, 10:2:7, 10:2:8,10:2:9, 10:2:10, 10:3:1, 10:3:2, 10:3:3, 10:3:4, 10:3:5, 10:3:6, 10:3:7,10:3:8, 10:3:9, 10:3:10, 10:4:1, 10:4:2, 10:4:3, 10:4:4, 10:4:5, 10:4:6,10:4:7, 10:4:8, 10:4:9, 10:4:10, 10:5:1, 10:5:2, 10:5:3, 10:5:4, 10:5:5,10:5:6, 10:5:7, 10:5:8, 10:5:9, 10:5:10, 10:6:1, 10:6:2, 10:6:3, 10:6:4,10:6:5, 10:6:6, 10:6:7, 10:6:8, 10:6:9, 10:6:10, 10:7:1, 10:7:2, 10:7:3,10:7:4, 10:7:5, 10:7:6, 10:7:7, 10:7:8, 10:7:9, 10:7:10, 10:8:1, 10:8:2,10:8:3, 10:8:4, 10:8:5, 10:8:6, 10:8:7, 10:8:8, 10:8:9, 10:8:10, 10:9:1,10:9:2, 10:9:3, 10:9:4, 10:9:5, 10:9:6, 10:9:7, 10:9:8, 10:9:9, 10:9:10,10:10:1, 10:10:2, 10:10:3, 10:10:4, 10:10:5, 10:10:6, 10:10:7, 10:10:8,10:10:9, 10:10:10, or any ratio in between. In view of the results anddiscussion contained herein, one of skill in the art would understandhow to formulate a combination composition comprising a curcumincomposition, as described herein, a green tea extract, as describedherein, and a phycocyanin composition, as described here, to achieve theresults described herein.

In certain embodiments, a combination composition can comprise about4.5:4.5:1 of diferuloylmethane to EGCG to phycocyanin or an extractthereof, about 6:3:1 of diferuloylmethane to EGCG to phycocyanin or anextract thereof, about 7.2:1.8:1 of diferuloylmethane to EGCG tophycocyanin or an extract thereof, or any ratio between about 8:1:1 toabout 1:8:1 of diferuloylmethane to EGCG to phycocyanin or an extractthereof.

In certain embodiments, a combination composition can comprise about4.5:4.5:1 of diferuloylmethane to EC to phycocyanin or an extractthereof, about 6:3:1 of diferuloylmethane to EC to phycocyanin or anextract thereof, about 7.2:1.8:1 of diferuloylmethane to EC tophycocyanin or an extract thereof, or any ratio between about 8:1:1 toabout 1:8:1 of diferuloylmethane to EC to phycocyanin or an extractthereof.

In certain embodiments, a combination composition can comprise about4.5:4.5:1 of diferuloylmethane to EGC to phycocyanin or an extractthereof, about 6:3:1 of diferuloylmethane to EGC to phycocyanin or anextract thereof, about 7.2:1.8:1 of diferuloylmethane to EGC tophycocyanin or an extract thereof, or any ratio between about 8:1:1 toabout 1:8:1 of diferuloylmethane to EGC to phycocyanin or an extractthereof.

In certain embodiments, a combination composition can comprise about4.5:4.5:1 of diferuloylmethane to ECG to phycocyanin or an extractthereof, about 6:3:1 of diferuloylmethane to ECG phycocyanin or anextract thereof, about 7.2:1.8:1 of diferuloylmethane to ECG tophycocyanin or an extract thereof, or any ratio between about 8:1:1 toabout 1:8:1 of diferuloylmethane to ECG to phycocyanin or an extractthereof.

In certain embodiments, a combination composition can comprise about4.5:4.5:1 of DMC to EGCG to phycocyanin or an extract thereof, about6:3:1 of DMC to EGCG to phycocyanin or an extract thereof, about7.2:1.8:1 of DMC to EGCG to phycocyanin or an extract thereof, or anyratio between about 8:1:1 to about 1:8:1 of DMC to EGCG to phycocyaninor an extract thereof.

In certain embodiments, a combination composition can comprise about4.5:4.5:1 of DMC to EC to phycocyanin or an extract thereof, about 6:3:1of DMC to EC to phycocyanin or an extract thereof, about 7.2:1.8:1 ofDMC to EC to phycocyanin or an extract thereof, or any ratio betweenabout 8:1:1 to about 1:8:1 of DMC to EC to phycocyanin or an extractthereof.

In certain embodiments, a combination composition can comprise about4.5:4.5:1 of DMC to EGC to phycocyanin or an extract thereof, about6:3:1 of DMC to EGC to phycocyanin or an extract thereof, about7.2:1.8:1 of DMC to EGC. to phycocyanin or an extract thereof, or anyratio between about 8:1+1 to about 1:8:1 of DMC to EGC to phycocyanin oran extract thereof.

In certain embodiments, a combination composition can comprise about4.5:4.5:1 of DMC to ECG to phycocyanin or an extract thereof, about6:3:1 of DMC to ECG to phycocyanin or an extract thereof, about7.2:1.8:1 of DMC to ECG to phycocyanin or an extract thereof, or anyratio between about 8:1:1 to about 1:8:1 of DMC to ECG to phycocyanin oran extract thereof.

In certain embodiments, a combination composition can comprise about4.5:4.5:1 of BDMC to EGCG to phycocyanin or an extract thereof, about6:3:1 of BDMC to EGCG to phycocyanin or an extract thereof, about7.2:1.8:1 of BDMC to EGCG to phycocyanin or an extract thereof, or anyratio between about 8:1:1 to about 1:8:1 of BDMC to EGCG to phycocyaninor an extract thereof.

In certain embodiments, a combination composition can comprise about4.5:4.5:1 of BDMC to EC to phycocyanin or an extract thereof, about6:3:1 of BDMC to EC to phycocyanin or an extract thereof, about7.2:1.8:1 of BDMC to EC to phycocyanin or an extract thereof, or anyratio between about 8:1:1 to about 1:8:1 of BDMC to EC to phycocyanin oran extract thereof.

In certain embodiments, a combination composition can comprise about4.5:4.5:1 of BDMC to EGC to phycocyanin or an extract thereof, about6:3:1 of BDMC to EGC to phycocyanin or an extract thereof, about7.2:1.8:1 of BDMC to EGC to phycocyanin or an extract thereof, or anyratio between about 8:1:1 to about 1:8:1 of BDMC to EGC to phycocyaninor an extract thereof.

In certain embodiments, a combination composition can comprise about4.5:4.5:1 of BDMC to ECG to phycocyanin or an extract thereof, about6:3:1 of BDMC to ECG to phycocyanin or an extract thereof, about7.2:1.8:1 of BDMC to ECG to phycocyanin or an extract thereof, or anyratio between about 8:1:1 to about 1:8:1 of BDMC to ECG to phycocyaninor an extract thereof.

In certain embodiments, a combination composition can comprise about4.5:4.5:1 of tetrahydrocurcumin to EGCG to phycocyanin or an extractthereof, about 6:3:1 of tetrahydrocurcumin to EGCG to phycocyanin or anextract thereof, about 7.2:1.8:1 of tetrahydrocurcumin to EGCG tophycocyanin or an extract thereof, or any ratio between about 8:1:1 toabout 1:8:1 of tetrahydrocurcumin to EGCG to phycocyanin or an extractthereof.

In certain embodiments, a combination composition can comprise about4.5:4.5: 1 of tetrahydrocurcumin to EC to phycocyanin or an extractthereof, about 6:3:1 of tetrahydrocurcumin to EC to phycocyanin or anextract thereof, about 7.2:1.8:1 of tetrahydrocurcumin to EC tophycocyanin or an extract thereof, or any ratio between about 8:1:1 toabout 1:8:1 of tetrahydrocurcumin to EC to phycocyanin or an extractthereof.

In certain embodiments, a combination composition can comprise about4.5:4.5:1 of tetrahydrocurcumin to EGC to phycocyanin or an extractthereof, about 6:3:1 of tetrahydrocurcumin to EGC to phycocyanin or anextract thereof, about 7.2:1.8:1 of tetrahydrocurcumin to EGC tophycocyanin or an extract thereof, or any ratio between about 8:1:1 toabout 1:8:1 of tetrahydrocurcumin to EGC to phycocyanin or an extractthereof.

In certain embodiments, a combination composition can comprise about4.5:4.5:1 of tetrahydrocurcumin to ECG to phycocyanin or an extractthereof, about 6:3:1 of tetrahydrocurcumin to ECG to phycocyanin or anextract thereof, about 7.2:1.8:1 of tetrahydrocurcumin to ECG tophycocyanin or an extract thereof, or any ratio between about 8:1:1 toabout 1:8:1 of tetrahydrocurcumin to ECG to phycocyanin or an extractthereof.

In certain embodiments, a combination composition can comprise about4.5:4.5:1 of dihydrocurcumin to EGCG to phycocyanin or an extractthereof, about 6:3:1 of dihydrocurcumin to EGCG to phycocyanin or anextract thereof, about 7.2:1.8:1 of dihydrocurcumin to EGCG tophycocyanin or an extract thereof, or any ratio between about 8:1:1 toabout 1:8:1 of dihydrocurcumin to EGCG to phycocyanin or an extractthereof.

In certain embodiments, a combination composition can comprise about4.5:4.5:1 of dihydrocurcumin to EC to phycocyanin or an extract thereof,about 6:3:1 of dihydrocurcumin to EC to phycocyanin or an extractthereof, about 7.2:1.8:1 of dihydrocurcumin to EC to phycocyanin or anextract thereof, or any ratio between about 8:1:1 to about 1:8:1 ofdihydrocurcumin to EC to phycocyanin or an extract thereof.

In certain embodiments, a combination composition can comprise about4.5:4.5:1 of dihydrocurcumin to EGC to phycocyanin or an extractthereof, about 6:3:1 of dihydrocurcumin to EGC to phycocyanin or anextract thereof, about 7.2:1.8:1 of dihydrocurcumin to EGC tophycocyanin or an extract thereof, or any ratio between about 8:1:1 toabout 1:8:1 of dihydrocurcumin to EGC to phycocyanin or an extractthereof.

In certain embodiments, a combination composition can comprise about4.5:4.5:1 of dihydrocurcumin to ECG to phycocyanin or an extractthereof, about 6:3:1 of dihydrocurcumin to ECG to phycocyanin or anextract thereof, about 7.2:1.8:1 of dihydrocurcumin to ECG tophycocyanin or an extract thereof, or any ratio between about 8:1:1 toabout 1:8:1 of dihydrocurcumin to ECG to phycocyanin or an extractthereof.

In certain embodiments, a combination composition can comprise about4.5:4.5:1 of hexahydrocurcumin to EGCG to phycocyanin or an extractthereof about 6:3:1 of hexahydrocurcumin to EGCG to phycocyanin or anextract thereof, about 7.2: 1.8:1 of hexahydrocurcumin to EGCG tophycocyanin or an extract thereof, or any ratio between about 8:1:1 toabout 1:8:1 of hexahydrocurcumin to EGCG to phycocyanin or an extractthereof.

In certain embodiments, a combination composition can comprise about4.5:4.5:1 of hexahydrocurcumin to EC to phycocyanin or an extractthereof, about 6:3:1 of hexahydrocurcumin to EC to phycocyanin or anextract thereof, about 7.2:1.8:1 of hexahydrocurcumin to EC tophycocyanin or an extract thereof, or any ratio between about 8:1:1 toabout 1:8:1 of hexahydrocurcumin to EC to phycocyanin or an extractthereof.

In certain embodiments, a combination composition can comprise about4.5:4.5:1 of hexahydrocurcumin to EGC to phycocyanin or an extractthereof, about 6:3:1 of hexahydrocurcumin to EGC to phycocyanin or anextract thereof, about 7.2:1.8:1 of hexahydrocurcumin to EGC tophycocyanin or an extract thereof, or any ratio between about 8:1:1 toabout 1:8:1 of hexahydrocurcumin to EGC to phycocyanin or an extractthereof.

In certain embodiments, a combination composition can comprise about4.5:4.5:1 of hexahydrocurcumin to ECG to phycocyanin or an extractthereof, about 6:3:1 of hexahydrocurcumin to ECG to phycocyanin or anextract thereof, about 7.2:1.8:1 of hexahydrocurcumin to ECG tophycocyanin or an extract thereof, or any ratio between about 8:1:1 toabout 1:8:1 of hexahydrocurcumin to ECG to phycocyanin or an extractthereof.

In certain embodiments, a combination composition can comprise about4.5:4.5: 1 of octahydrocurcumin to EGCG to phycocyanin or an extractthereof, about 6:3:1 of octahydrocurcumin to EGCG to phycocyanin or anextract thereof, about 7.2:1.8:1 of octahydrocurcumin to EGCG tophycocyanin or an extract thereof, or any ratio between about 8:1:1 toabout 1:8:1 of octahydrocurcumin to EGCG to phycocyanin or an extractthereof.

In certain embodiments, a combination composition can comprise about4.5:4.5:1 of octahydrocurcumin to EC to phycocyanin or an extractthereof, about 6:3:1 of octahydrocurcumin to EC to phycocyanin or anextract thereof, about 7.2:1.8:1 of octahydrocurcumin to EC tophycocyanin or an extract thereof, or any ratio between about 8:1:1 toabout 1:8:1 of octahydrocurcumin to EC to phycocyanin or an extractthereof.

In certain embodiments, a combination composition can comprise about4.5:4.5:1 of octahydrocurcumin to EGC to phycocyanin or an extractthereof, about 6:3:1 of octahydrocurcumin to EGC to phycocyanin or anextract thereof, about 7.2: 1.8:1 of octahydrocurcumin to EGC tophycocyanin or an extract thereof, or any ratio between about 8:1:1 toabout 1:8:1 of octahydrocurcumin to EGC to phycocyanin or an extractthereof.

In certain embodiments, a combination composition can comprise about4.5:4.5:1 of octahydrocurcumin to ECG to phycocyanin or an extractthereof, about 6:3:1 of octahydrocurcumin to ECG to phycocyanin or anextract thereof, about 7.2:1.8:1 of octahydrocurcumin to ECG tophycocyanin or an extract thereof, or any ratio between about 8:1:1 toabout 1:8:1 of octahydrocurcumin to ECG to phycocyanin or an extractthereof.

In some embodiments, a combination composition, as described herein, maycomprise between about 10 µg to about 10 g of one or more of a curcumincomposition, as described herein, a green tea extract composition, asdescribed herein, and a phycocyanin composition, as described herein.For example, some embodiments include a combination compositioncomprising one or more of a of a curcumin composition, as describedherein, a green tea extract composition, as described herein, and aphycocyanin composition, as described herein present at an amount ofabout 10 µg, 15 µg, 20 µg, 25 µg, 30 µg, 35 µg, 40 µg, 45 µg, 50 µg, 55µg, 60 µg, 65 µg, 70 µg, 75 µg, 80 µg, 85 µg, 90 ug, 95 µg, 100 µg, 125µg, 150 µg, 175 µg, 200 µg, 225 µg, 250 µg, 275 µg, 300 µg, 325 µg, 350µg, 375 µg, 400 ug, 425 µg, 450 µg, 475 µg, 500 µg, 525 µg, 575 µg, 600µg, 625 µg, 650 µg, 675 µg, 700 µg, 725 µg, 750 µg, 775 µg, 800 µg, 825µg, 850 µg, 875 µg, 900 µg, 925 µg, 950 µg, 975 µg, 1000 µg, 5 mg, 10mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 125 mg, 150mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg , 975 mg, 1000 mg, 2 g, 3 g,4 g, 5 g, 6 g, 7 g, 8 g, 9 g, 10 g, or any range or amount in betweenany two of the preceding values and any other ranges or amountsdisclosed herein.

In some embodiments, a curcumin composition, a green tea extractcomposition, a phycocyanin composition, or a combination composition, asdescribed herein, can comprise one or more supplement ingredients. Asused herein, the term supplement ingredient can refer to essential fattyacids such as linolenic acid and linoleic acid, and essential aminoacids such as tryptophan, lysine, methionine, phenylalanine, threonine,valine, leucine, isoleucine, arginine, and histidine, and n-acetylcysteine. Also included within the meaning of supplement ingredients arevitamins such as retinol (vitamin A), thiamine (vitamin B1), riboflavin(vitamin B2), niacin (vitamin B3), pantothenic acid (vitamin B5),pyridoxine, pyridoxamine, or pyridoxal (vitamin B6), biotin (vitamin B7)or pharmaceutically acceptable salts thereof, folic acid (vitamin B9) orpharmaceutically acceptable salts thereof, cobalamin (vitamin B12),choline, ascorbic acid (vitamin C) or pharmaceutically acceptable saltsthereof, ergocalciferol (vitamin D2), calciferol (vitamin D3),22-dihydroergocalciferol (vitamin D4), sitocalciferol (vitamin D5),tocopherol (vitamin E), phylloquinone (vitamin K1), menaquinone (vitaminK2), menadione (vitamin K3), or any combination of the foregoing. Othervitamins not explicitly listed would readily be envisaged by those ofskill in the art, in view of the disclosure contained herein. Supplementingredients can further include dietary minerals such as, for example,chromium, bromine, cobalt, copper, fluorine, germanium, iodine, iron,magnesium, manganese, molybdenum, potassium, selenium, silicon, zinc,calcium, phosphorous, sodium, sulfur, and vanadium. Supplementingredients can also comprise cranberry extract, turmeric, royal jelly,açaí berry, beet root, coral calcium, oyster shell, gotu kola, Gingkobiloba, lions mane mushroom, pomegranate, hibiscus flower, strawberrypowder, dandelion root, celery powder, parsley powder, peppermint leaf,cinnamon bark powder, maca root, nicotinamide riboside, resveratrol,NAD+ precursors, Coenzyme Q10, omega-3-fatty acids, cabbage powder,pterostilbene, nicotinamide mononucleotide, and combinations thereof.Supplement ingredients can include nitrates such as citrulline nitrate,creatine nitrate, beta-alanine nitrate, and the like. Compositionsdescribed herein can include one or more of the foregoing supplementingredients, as would be understood by one of skill in the art.

In some embodiments, an amount of least one supplemental ingredient, asdisclosed herein, can be about 10 µg to about 10 g. For example, theamount of the at least one supplemental ingredient in the compositioncan be about 10 µg, 15 µg, 20 µg, 25 µg, 30 µg, 35 µg, 40 µg, 45 µg, 50µg, 55 µg, 60 µg, 65 µg, 70 µg, 75 µg, 80 µg, 85 µg, 90 µg, 95 µg, 100µg, 125 µg, 150 µg, 175 µg, 200 µg, 225 µg, 250 µg, 275 µg, 300 µg, 325µg, 350 µg, 375 µg, 400 µg, 425 µg, 450 µg, 475 µg, 500 µg, 525 µg, 575µg, 600 µg, 625 µg, 650 µg, 675 µg, 700 µg, 725 µg, 750 µg, 775 µg, 800µg, 825 µg, 850 µg, 875 µg, 900 µg, 925 µg, 950 µg, 975 µg, 1000 µg, 5mg, 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg,225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg,450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg,675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg,900 mg, 925 mg, 950 mg, 975 mg, 1000 mg, 2 g, 3 g, 4 g, 5 g, 6 g, 7 g, 8g, 9 g, 10 g, or any range or amount in between any two of the precedingvalues and any other ranges or amounts disclosed herein.

In certain embodiments, a curcumin composition, a green tea extractcomposition, a phycocyanin composition, or a combination composition, asdescribed herein, can be formulated as a dietary supplement orpharmaceutical agent.

The compounds comprising curcumin compositions, green tea extractcompositions, and phycocyanin compositions, as described herein, may bean active agent present in a therapeutically effective amount. By way ofexample, a “therapeutically effective amount” and/or an “effectiveamount” of the compound disclosed herein can be (on a dosage weight persubject weight basis), for example, 0.1 µg/kg, 0.5 µg/kg, 1 µg/kg, 1.5µg/kg, 2.0 µg/kg, 2.5 µg/kg, 3.0 µg/kg, 3.5 µg/kg, 4.0 µg/kg, 4.5 µg/kg,5.0 µg/kg, 10 µg/kg, 15 µg/kg, 20 µg/kg, 25 µg/kg, 30 µg/kg, 35 µg/kg,40 µg/kg, 45 µg/kg, 50 µg/kg, 55 µg/kg, 60 µg/kg, 65 µg/kg, 70 µg/kg, 75µg/kg, 80 µg/kg, 85 µg/kg, 90 µg/kg, 95 µg/kg, 100 µg/kg, 150 µg/kg, 200µg/kg, 250 µg/kg, 300 µg/kg, 350 µg/kg, 400 µg/kg, 450 µg/kg, 500 µg/kg,550 µg/kg, 600 µg/kg, 650 µg/kg, 700 µg/kg, 750 µg/kg, 80 µg/kg 0, 850µg/kg, 900 µg/kg, 1 mg/kg, 1.5 mg/kg, 2.0 mg/kg, 2.5 mg/kg, 3 mg/kg, 3.5mg/kg, 4.0 mg/kg, 4.5 mg/kg, 5 mg/kg, 5.5 mg/kg, 6 mg/kg, 6.5 mg/kg, 7mg/kg, 7.5 mg/kg, 8 mg/kg, 8.5 mg/kg, 9 mg/kg, 9.5 mg/kg, 10 mg/kg 10.5mg/kg, 11 mg/kg, 11.5 mg/kg, 12 mg/kg, 12.5 mg/kg, 13 mg/kg, 13.5 mg/kg,14 mg/kg, 14.5 mg/kg, 15 mg/kg, 16 mg/kg, 17 mg/kg, 18 mg/kg, 19 mg/kg,20 mg/kg, 21 mg/kg, 22 mg/kg, 23 mg/kg, 24 mg/kg, 25 mg/kg, 30 mg/kg, 35mg/kg, 40 mg/kg, 45 mg/kg, 50 mg/kg, 55 mg/kg, 60 mg/kg, 65 mg/kg, 70mg/kg, or more, or any fraction or integer in between any two of thepreceding amounts of the compound. An effective amount may include anyof the ranges and amounts discussed herein.

Accordingly, in some embodiments, the dose of the compound incompositions disclosed herein (corresponding to the therapeuticallyeffective amount), can be about 10 µg to about 10 g, preferably per day.For example, the amount of the composition can be 10 µg, 15 µg, 20 µg,25 µg, 30 µg, 35 µg, 40 µg, 45 µg, 50 µg, 55 µg, 60 µg, 65 µg, 70 µg, 75µg, 80 µg, 85 µg, 90 µg, 95 µg, 100 µg, 125 µg, 150 µg, 175 µg, 200 µg,225 µg, 250 µg, 275 µg, 300 µg, 325 µg, 350 µg, 375 µg, 400 µg, 425 µg,450 µg, 475 µg, 500 µg, 525 µg, 575 µg, 600 µg, 625 µg, 650 µg, 675 µg,700 µg , 725 µg, 750 µg, 775 µg, 800 µg, 825 µg, 850 µg, 875 µg, 900 µg,925 µg, 950 µg, 975 µg, 1000 µg, 1.25 g, 1.5 g, 1.75 g, 2.0 g, 2.25 g,2.5 g, 2.75 g, 3.0 g, 3.25 g, 3.5 g, 3.5 g, 3.75 g, 4.0 g, 4.25 g, 4.5g, 4.75 g, 5.0 g, 5.25 g, 5.5 g, 5.75 g, 6.0 g, 6.25 g, 6.5 g, 6.75 g,7.0 g, 7.25 g, 7.5 g, 7.75 g, 8.0 g, 8.25 g, 8.5 g, 8.75 g, 9.0 g, 8.25g, 9.5 g, 9.75 g, 10 g, or more, or any range or amount in between anytwo of the preceding values and any other ranges or amounts disclosedherein.

In some embodiments, a curcumin composition, as described herein, agreen tea extract composition, as described herein, and a phycocyanincomposition, as described herein, are provided in a synergistic ratio ina combination composition, and optionally, the combination compositionmay be provided as a dietary supplement or pharmaceutical agent. Thesynergistic ratio is not particularly limited. In some embodiments thesynergistic ratio can comprise 4.5:4.5:1 of curcumin composition togreen tea extract composition to phycocyanin composition. In someembodiments the synergistic ratio can comprise 6:3:1 of curcumincomposition to green tea extract composition to phycocyanin composition.In some embodiments the synergistic ratio can comprise 7.2:1.8:1 ofcurcumin composition to green tea extract composition to phycocyanincomposition. In some embodiments the synergistic can comprise any ratiobetween about 8:1:1 to about 1:8:1 of curcumin composition to green teaextract composition phycocyanin composition.

In some embodiments, compositions, as described herein, can beadministered in the methods described elsewhere herein on an hourlybasis, e.g., every one, two, three, four, five, six, seven, eight, nine,ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen,eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three hours,or any interval in between, or on a daily basis, every two days, everythree days, every four days, every five days, every six days, everyweek, every eight days, every nine days, every ten days, every twoweeks, every month, or more or less frequently, as needed to achieve thedesired therapeutic effect.

In some embodiments, a ramping administration protocol where a subjectis administered temporally increasing amounts of compositions describedherein can be utilized. For example, a subject could be administeredwith 100 mg of a composition as described herein per day for 7 days,followed by 200 mg, for the next 7 days, followed by 300 mg for the next7 days. Administration protocols can also follow a pattern whereby thedosage amount decreases over time. For example, 300 mg of a compositionas described herein per day for 7 days, followed by 200 mg, for the next7 days, followed by 100 mg for the next 7 days. In some embodiments, themethods as described herein can be utilized in combination with acalorie restriction protocol in a subject. In certain embodiments, thecompositions described herein may be administered before, after, orduring a meal. In addition, the appropriate dosage of the compositionscan depend, for example, on the condition to be treated, the severityand course of the condition, whether the composition is administered forpreventive or therapeutic purposes, previous therapy, the patient’sclinical history and response to the composition, the type ofcomposition used, and the discretion of the attending physician. Thecomposition can be suitably administered to the patient at one time orover a series of treatments and may be administered to the patient atany time from diagnosis onwards. The composition may be administered asthe sole treatment or in conjunction with other drugs or therapiesuseful in treating the condition in question.

The present disclosure discloses combination compositions comprising oneor more of a curcumin composition, a green tea extract composition, anda phycocyanin composition, optionally formulated as a nutritionalsupplement or pharmaceutical agent, useful as an NK3 antagonist, andmethods of using the same. Some embodiments provide solid dosage formsof the compositions disclosed herein. Certain embodiments provideaqueous solutions of compositions disclosed herein. Embodimentsdescribed herein comprising compositions disclosed herein as anutritional supplement means that the composition disclosed herein ispresent in an unnatural form, i.e., is presented in a supplement (e.g.,in a pill or powder) that is different from that which occurs naturally,or the nutritional or dietary supplement results in unnaturalsupplementation that is unachievable through a non-supplemented diet.Some embodiments can further comprise a matrix material such as a fattyacid, fatty acid ester, triglycerides, oils, lipid solvents, and thelike. In some embodiments, a composition is a solid composition. In someembodiments, the composition comprises a sustained-release matrix. Insome embodiments, the composition is enteric coated.

Some embodiments provide physiologically compatible compositions, asdisclosed herein, including hydrates, crystalline forms, polymorphicforms, solid forms having specific bulk densities or tap densities, andsolid forms having specific particle sizes. Some embodiments providecompositions coated with pharmaceutically acceptable materials intendedto modify its release and/or bioavailability, including, but not limitedto Eudragit®, microcrystalline cellulose, hydroxypropylmethylcellulosephthalate, and the like.

For oral administration, the compositions disclosed herein can beprovided as a tablet, aqueous or oil suspension, dispersible powder orgranule, emulsion, hard or soft capsule, syrup, elixir, or beverage.Solid dosage forms such as tablets and capsules may comprise an entericcoating. Compositions intended for oral use can be prepared according toany method known in the art for the manufacture of pharmaceuticallyacceptable compositions and such compositions may include one or more ofthe following agents: sweeteners, flavoring agents, coloring agents,coatings, and preservatives. The sweetening and flavoring agents willincrease the palatability of the preparation. Tablets containing thecomplexes in admixture with non-toxic pharmaceutically acceptableexcipients suitable for tablet manufacture are acceptable.Pharmaceutically acceptable vehicles such as excipients are compatiblewith the other ingredients of the formulation (as well as non-injuriousto the patient). Such excipients include inert diluents such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, such as corn starch oralginic acid; binding agents such as starch, gelatin, or acacia; andlubricating agents such as magnesium stearate, stearic acid or talc.Tablets can be uncoated or can be coated by known techniques to delaydisintegration and absorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period of time. For example, atime delay material such as glyceryl monostearate or glyceryl distearatealone or with a wax can be employed.

Formulations for oral use can also be presented as hardgelatin-containing or non-gelatinous capsules wherein the activeingredient is mixed with an inert solid diluent, for example calciumcarbonate, calcium phosphate or kaolin, or as soft gelatin capsuleswherein the active ingredient is mixed with water or an oil medium, suchas peanut oil, liquid paraffin, or olive oil. Aqueous suspensions cancontain the complex of the described herein admixed with excipientssuitable for the manufacture of aqueous suspensions. Such excipientsinclude suspending agents, dispersing, or wetting agents, one or morepreservatives, one or more coloring agents, one or more flavoring agentsand one or more sweetening agents such as sucrose or saccharin.

Oil suspensions can be formulated by suspending the active ingredient ina vegetable oil, such as arachis oil, olive oil, sesame oil or coconutoil, or in a mineral oil such as liquid paraffin. The oil suspension cancontain a thickening agent, such as beeswax, hard paraffin or cetylalcohol. Sweetening agents, such as those set forth above, and flavoringagents can be added to provide a palatable oral preparation. Thesecompositions can be preserved by an added antioxidant such as ascorbicacid. Dispersible powders and granules suitable for preparation of anaqueous suspension by the addition of water can provide the activeingredient in admixture with a dispersing or wetting agent, a suspendingagent, and one or more preservatives. Additional excipients, for examplesweetening, flavoring, and coloring agents, can also be present.

Syrups and elixirs can be formulated with sweetening agents, such asglycerol, sorbitol, or sucrose. Such formulations can also contain ademulcent, a preservative, a flavoring, or a coloring agent.

The composition for parenteral administration can be in the form of asterile injectable preparation, such as a sterile injectable aqueous oroleaginous suspension. This suspension can be formulated according tomethods well known in the art using suitable dispersing or wettingagents and suspending agents. The sterile injectable preparation canalso be a sterile injectable solution or suspension in a non-toxicparenterally-acceptable diluent or solvent, such as a solution in1,3-butanediol. Suitable diluents include, for example, water, Ringer’ssolution, and isotonic sodium chloride solution. In addition, sterilefixed oils can be employed conventionally as a solvent or suspendingmedium. For this purpose, any bland fixed oil can be employed includingsynthetic mono or diglycerides. In addition, fatty acids such as oleicacid can likewise be used in the preparation of injectable preparations.

It will be appreciated that the amount of the compound may be combinedwith a carrier material to produce a single dosage form. Such forms willvary depending upon the host treated and the particular mode ofadministration.

In some aspects, compositions described herein may be administered viasupplements or dosages designed for animals. In some animalapplications, the compound or composition may be added to and/orcomprise a pet treat or biscuit, for example, a dog biscuit or a cattreat.

Aqueous suspensions may contain the compound disclosed herein inadmixture with excipients suitable for the manufacture of aqueoussuspensions. Such excipients include suspending agents, dispersing, orwetting agents, one or more preservatives, one or more coloring agents,one or more flavoring agents and one or more sweetening agents such assucrose or saccharin.

Utilization of controlled release vehicles would readily be envisaged bythose of skill in the pharmaceutical sciences in view of the disclosurecontained herein, and these aspects can be applied to nutritional anddietary supplements. The technology and products in this art arevariably referred to as controlled release, sustained release, prolongedaction, depot, repository, delayed action, retarded release, and timedrelease; the words “controlled release” as used herein is intended toincorporate each of the foregoing technologies.

Numerous controlled release vehicles can be used, includingbiodegradable or bioerodable polymers such as polylactic acid,polyglycolic acid, and regenerated collagen. Controlled release drugdelivery devices can include creams, lotions, tablets, capsules, gels,microspheres, liposomes, ocular inserts, minipumps, and other infusiondevices such as pumps and syringes. Implantable or injectable polymermatrices, and transdermal formulations, from which active ingredientsare slowly released, and can be used in the disclosed methods.

Controlled release preparations can be achieved by the use of polymersto form complexes with or absorb a curcumin composition. The controlleddelivery can be exercised by selecting appropriate macromolecules suchas polyesters, polyamino acids, polyvinylpyrrolidone, ethylenevinylacetate, methylcellulose, carboxymethylcellulose, and protamine sulfate,and the concentration of these macromolecule as well as the methods ofincorporation are selected in order to control release of activecomplex.

Controlled release of active complexes can be taken to mean any of theextended release dosage forms. The following terms may be considered tobe substantially equivalent to controlled release, for the purposes ofthe present disclosure: continuous release, controlled release, delayedrelease, depot, gradual release, long term release, programmed release,prolonged release, programmed release, proportionate release, protractedrelease, repository, retard, slow release, spaced release, sustainedrelease, time coat, time release, delayed action, extended action,layered time action, long acting, prolonged action, sustained actionmedications and extended release, release in terms of pH level in thegut and intestine, breakdown of the molecule and based on the absorptionand bioavailability.

Hydrogels, wherein a composition as disclosed herein is dissolved in anaqueous constituent to gradually release over time, can be prepared bycopolymerization of hydrophilic mono-olefinic monomers such as ethyleneglycol methacrylate. Matrix devices, wherein a curcumin composition isdispersed in a matrix of carrier material, can be used. The carrier canbe porous, non-porous, solid, semi-solid, permeable, or impermeable.Alternatively, a device comprising a central reservoir of a compositiondisclosed herein surrounded by a rate controlling membrane can be usedto control the release of the complex. Rate controlling membranesinclude ethylene-vinyl acetate copolymer or butyleneterephthalate/polytetramethylene ether terephthalate. Use of siliconrubber or ethylene-vinyl alcohol depots are also contemplated.

Controlled release oral formulations can also be used. In an embodiment,a composition as described herein is incorporated into a soluble orerodible matrix, such as a pill or a lozenge. In another example, theoral formulations can be a liquid used for sublingual administration.These liquid compositions can also be in the form a gel or a paste.Hydrophilic gums, such as hydroxymethylcellulose, are commonly used. Alubricating agent such as magnesium stearate, stearic acid, or calciumstearate can be used to aid in the tableting process.

In some embodiments, dosing for oral administration may be with aregimen calling for single daily dose, or for a single dose every otherday, or for a single dose within 72 hours of the first administereddose, or for multiple, spaced doses throughout the day. The activeagents which make up the therapy may be administered simultaneously,either in a combined dosage form or in separate dosage forms intendedfor substantially simultaneous oral administration. The active agentswhich make up the therapy may also be administered sequentially, witheither active component being administered by a regimen calling fortwo-step ingestion. Thus, a regimen may call for sequentialadministration of the active agents with spaced-apart ingestion of theseparate, active agents. The time period between the multiple ingestionsteps may range from a few minutes to as long as about 72 hours,depending upon the properties of each active agent such as potency,solubility, bioavailability, plasma half-life and kinetic profile of theagent, as well as depending upon the age and condition of the patient.The active agents of the therapy whether administered simultaneously,substantially simultaneously, or sequentially, may involve a regimencalling for administration of one active agent by oral route and theother active agent by intravenous route. In one aspect, the embodimentsdescribed herein can achieve therapeutic and/or nutraceutical benefitsnot previously recognized or achievable, and thus, unexpectedly, andsurprisingly achieve improved abilities for using the compositions. Insome embodiments a composition is formulated for intravenousadministration because a more concentrated solution can be produced.Whether the active agents of the therapy are administered by oral orintravenous route, separately or together, each such active agent willbe contained in a suitable pharmaceutical formulation ofpharmaceutically-acceptable excipients, diluents, or other formulationscomponents.

In certain embodiments, a combination composition according to thedisclosure contained herein is administered to a subject as an NK3antagonist. In certain embodiments, a composition, as described herein,is administered to a subject to treat, ameliorate, prevent, or reducethe effects of polycystic ovary syndrome. In certain embodiments, acomposition as described herein is administered to a subject to supportand/or maintain healthy levels of NK3 antagonism. In certainembodiments, a composition, as described herein, is administered to asubject to treat, ameliorate, prevent, or reduce the effects ofinfertility in women, hirsutism, acne, obesity, chronic anovulation,metabolic syndrome, type II diabetes mellitus, and combinations thereof.In certain embodiments, a composition, as described herein, isadministered to support and/or maintain healthy fertility in women. Insome embodiments, a composition, as described herein, is administered incombination with metabolic modulators such as metformin. In certainembodiments, a composition, as described herein, is administered to asubject to treat, ameliorate, prevent, or reduce the effects ofcardiovascular disease and/or hypertension. In certain embodiments, acomposition, as described herein, is administered to a subject tosupport and/or maintain healthy stress levels. In certain embodiments awoman with a body mass index exceeding 15 kg/m² and identified to havepolycystic ovary syndrome is administered a composition, as describedherein, to treat, ameliorate, prevent, or reduce the effects ofpolycystic ovary syndrome. In some embodiments, a composition, asdescribed herein, is administered in combination with luteinizinghormone (LH) is administered to a subject to treat, ameliorate, prevent,or reduce the effects of one or more of the ailments described herein.In some embodiments, a composition, as described herein, is administeredto a subject to treat, ameliorate, prevent, or reduce the effects of hotflashes. In some embodiments, a composition, as described herein, isadministered to a menopausal woman to maintain a healthy level of hotflashes, i.e., to reduce the number, frequency, and/or severity of hotflashes.

Without being bound by any particular theory, it is believed that thecompositions and/or dietary supplements disclosed herein act asantagonists by targeting signaling pathways associated with menopause.It is believed that the symptoms associated with menopause arecharacterized by, and result from, increased secretion of LH andfollicle-stimulating hormone (FSH) from the pituitary gland. Theincrease in LH and FSH secretion is believed to be mediated by increasedsecretion of gonadotropin hormone-releasing hormone (GnRH) and resultingfrom increased kisspeptin and NKB signaling. Accordingly, it is believedthat by blocking and/or restricting the increased signaling ofkisspeptin and NKB in their associated pathways, with antagonists, theincreased secretion of GnRH can be reduced, and ultimately the secretionof LH and FSH. By reducing secretion of LH and FSH, it is believed thatthe symptoms associated with menopause can treated, prevented,ameliorated, and/or the effects associated therewith can be reduced.

In some embodiments, a composition as described herein is administeredto a subject to treat, ameliorate, prevent, or reduce the effects ofmental, psychotic, and/or neuropsychiatric disorders such asschizophrenia, cognitive decline during aging, dementia, depression,Alzheimer’s, and the like. In some embodiments, a composition asdescribed herein is administered to support and/or maintain healthycognitive function. In certain embodiments, a composition as describedherein is administered to a subject to treat, ameliorate, prevent, orreduce the effects of neuroinflammation. In some embodiments, acomposition as described herein is administered in combination with anantipsychotic drug, including but not limited to, aripiprazole,clozapine, olanzapine, risperidone, ziprasidone, quetiapine,haloperidol, osanetant, and/or talnetant. In some embodiments, acomposition as described herein is administered to a subject to treat,ameliorate, prevent, or reduce the effects of drug, nicotine, and/oralcohol addiction. In some embodiments, composition as described hereinis administered to a subject to reduce drug-seeking behavior.

In some embodiments, a composition as described herein is administeredto a subject to treat, ameliorate, prevent, or reduce the effects ofdisorders associated with inflammation. For example, and withoutlimitation, this includes central nervous system disorders (e.g.,anxiety, psychosis, movement and convulsive disorders, and Parkinson’s),respiratory and pulmonary inflammatory disorders, skin disorders anditch, gastrointestinal disorders, renal and bladder diseases,inflammatory bowel disease, eating disorders, and chronic pain. Incertain embodiments, a curcumin composition is administered to treathormonal variations.

As used herein, “identifying,” refers to detecting or selecting asubject from a population of potential subjects, for example, toestablish that a particular subject possesses certain properties orcharacteristics. “Identifying” may include, for example,self-identification, self-diagnosis, and diagnosis by a medicalprofessional.

As used herein, the terms “prophylactic treatment,” “prevent,” or“preventing,” can refer to treating a subject who does not yet exhibitsymptoms of a disease or condition, but who is susceptible to, orotherwise at risk of, a particular disease or condition, whereby thetreatment reduces the likelihood that the patient will develop thedisease or condition. A “disorder” is any condition that would benefitfrom treatment with the compositions described herein.

As used herein, the terms “treating”, “treatment” and the like are usedherein to generally refer to obtaining a desired pharmacological andphysiological effect and can also refer to a nutritional ornutraceutical effect, the scopes, and meanings of which will be clear tothe skilled artisan based upon the context in which these terms areused. The effect may be prophylactic in terms of preventing or partiallypreventing a disease, symptom, or condition thereof and/or may betherapeutic in terms of a partial or complete cure of a disease,condition, symptom, or adverse effect attributed to the disease. Theterm “treatment” as used herein encompasses any treatment of a diseasein a mammal, particularly a human and includes: (a) preventing thedisease from occurring in a subject which may be predisposed to thedisease but has not yet been diagnosed as having it; (b) inhibiting thedisease or arresting its development; or (c) relieving the disease,causing regression of the disease and/or its symptoms, conditions, andco-morbidities. The terms “optimum” or “healthy” and the like may beused to refer to the physiological amounts of NK3 activity in a mammal,wherein administration of compositions as described herein may beadministered to a mammal that may not have a disease or symptoms of adisease associated with NK3 activity but may be administered toantagonize NK3 along with the other physiological results describedherein.

As used in the claims below and throughout this disclosure, the phrase“consisting essentially of” is meant including any elements listed afterthe phrase and limited to other elements that do not interfere with orcontribute to the activity or action specified in the disclosure for thelisted elements. Thus, the phrase “consisting essentially of” indicatesthat the listed elements are required or mandatory, but that otherelements are optional and can or cannot be present depending uponwhether or not they affect the activity or action of the listedelements. For example, the use of a composition “consisting essentiallyof a composition” for the treatment of a particular disease or disorder,or the maintenance of a healthy condition, would exclude otheringredients that would materially alter the intended outcome of thecurcumin composition.

As used herein, the meaning of the term “hot flash” would immediately beenvisaged by the skilled artisan. The etiology of hot flashes would beunderstood by the skilled artisan to refer to the sudden feeling ofwarmth, usually most intense over the face, neck, and chest, and profusesweating, which is most commonly due to menopause. However, compositionsdescribed herein can also be administered to treat, ameliorate, prevent,or reduce the effects of hot flashes that are not caused by menopause.

As used herein, a composition that “substantially” comprises a compoundmeans that the composition contains more than about 80% by weight, morepreferably more than about 90% by weight, even more preferably more thanabout 95% by weight, and most preferably more than about 98% by weightof the compound.

The term “pharmaceutical formulation”, “formulation”, “composition” andthe like can refer to preparations which are in such a form as to permitthe biological activity of the active ingredients to be effective, andtherefore may be administered to a subject for therapeutic use alongwith dietary and/or nutritional supplement use. The meaning of theseterms will be clear to the skilled artisan based upon the context inwhich they are used.

A “therapeutically effective amount” as used herein includes within itsmeaning a non-toxic but sufficient amount of a compound activeingredient or composition comprising the same for use in the embodimentsdisclosed herein to provide the desired therapeutic effect. Similarly,“an amount effective to” or “an effective amount” as used hereinincludes within its meaning a non-toxic but sufficient amount of acompound active ingredient or composition comprising the same to providethe desired effect. A “therapeutically effective amount” or an“effective amount” includes amounts of compounds that would not beachievable through a standard diet, but requires supplementation anddosing as described herein. The exact amount of the active ingredientdisclosed herein required will vary from subject to subject depending onfactors such as the species being treated, the age and general conditionof the subject, the severity of the condition being treated, theparticular agent being administered, the weight of the subject, and themode of administration and so forth. Thus, it may not always be possibleto specify an exact “effective amount.” However, for any given case, anappropriate “effective amount” may be determined by one of ordinaryskill in the art in view of the disclosure contained herein. In someaspects, a therapeutically effective amount may include a dosingregimen. For example, a therapeutically effective amount may includeabout 100 mg of a curcumin composition orally consumed each day forfourteen consecutive days. In some aspects, a therapeutically effectiveamount may include about 100 mg of a composition orally consumed eachday for thirty consecutive days. Compositions including a compositionmay include, for example, between 0.1-1000 grams of the composition.

As used herein, the terms “synergy”, “synergistic”, “synergism” and thelike are used herein to generally refer to the therapeutic efficacy ofthe composition being at least equal to the sum of the efficacy of theindividual components in the composition administered independently.“Synergy”, “synergistic”, “synergism” and the like may also refer to thetherapeutic efficacy of a composition being greater than the sum of theefficacy of the individual components in the composition administeredindependently. The scopes and meanings of which will be clear to theskilled artisan based upon the context in which these terms are used.

As provided herein, the disclosure of a “ratio” of compounds andcompositions corresponds to a ratio provided in terms of mass of thecomponents present in the ratio.

As used herein, the term “pharmaceutically acceptable solvent” can referto water, water for injection, aqueous buffer solutions that arephysiologically compatible, or aqueous solutions containing organicsolvents that are physiologically compatible. A non-comprehensive listof pharmaceutically acceptable solvents is provided in U.S. Departmentof Health & Human Services, Food & Drug Administration, “Guidance forIndustry: Q3C Impurities: Residual Solvents,” December 1997 or itscurrent issue.

As used herein, the term “bioavailability” refers to the amount of asubstance that is absorbed in the intestines and ultimately availablefor biological activity in a subject’s tissue and cells.

As used herein, the term “enhancing the bioavailability” and the likeare used herein to refer to obtaining a desired pharmacological and/orphysiological effect of antagonizing NK3 that is absorbed from theintestine or is taken up by tissues and cells after administration of acomposition to a mammal, which does not occur naturally. The effect maybe prophylactic in terms of preventing or partially preventing theincidence, risk, or severity of an adverse symptom or condition causedby or related to the deficiency of a therapeutic agent.

As used herein, the term “excipient material” refers to any compoundthat is part of a formulation that is not an active ingredient, i.e.,one that has no relevant biological activity, and which is added to theformulation to provide specific characteristics to the dosage form,including by way of example, providing protection to the activeingredient from chemical degradation, facilitating release of a tabletor caplet from equipment in which it is formed, and so forth.

For the purpose of this disclosure, a warm-blooded animal is a member ofthe animal kingdom which includes but is not limited to mammals andbirds. In certain embodiments described herein, a mammal may, forexample but without limitation, be a horse, dog, or cat. The mostpreferred mammal of this application is a human.

To provide a more concise description, some of the quantitativeexpressions given herein are not qualified with the term “about.” It isunderstood that whether the term “about” is used explicitly or not,every quantity given herein is meant to refer to the actual given value,and it is also meant to refer to the approximation to such given valuethat would reasonably be inferred based on the ordinary skill in theart, including approximations due to the experimental and/or measurementconditions for such given value.

While the present invention has been described in some detail forpurposes of clarity and understanding, one will appreciate that variouschanges in form and detail can be made without departing from the truescope of the invention.

EXAMPLES Example 1 Method

The NK3 antagonistic activity of compositions disclosed herein werestudied at the human NK3 receptor expressed in transfected CHO cells.The antagonistic activity was determined by measuring their effect onNeurokinin B (NKB, a potent NK3 agonist)-induced cytosolic Ca²⁺ ionmobilization using a fluorometric detection method. Several ingredientswere administered to transfected CHO cells, the results of which areshown in FIGS. 1A-1C, and described further below.

Experimental Protocol

The CHO cells were suspended in DMEM buffer (Invitrogen) complementedwith 0.1% FCSd, then distributed in microplates at a density of 3 × 10⁴cells/well. The fluorescent probe (Fluo4 Direct, Invitrogen) was mixedwith probenecid in HBSS buffer (Invitrogen) complemented with 20 mMHEPES (Invitrogen) (pH 7.4) is then added into each well andequilibrated with the cells for 60 min at 37° C. then 15 min at 22° C.

Thereafter, the assay plates were positioned in a microplate reader(CellLux, PerkinElmer) which was used for the addition of the testitems, curcumin extract as defined herein, or HBSS buffer, followed bythe addition (5 min later) of 1 nM [MePhe7]-NKB or HBSS buffer (basalcontrol). Next, the changes in fluorescence intensity was determinedwhich varies proportionally to the free cytosolic Ca²⁺ ionconcentration. The standard reference antagonist is SB 222200, which wastested at several concentrations to generate a concentration-responsecurve from which its IC50 value is calculated.

The results are expressed as a percent inhibition of the controlresponse to 1 nM [MePhe7]-NKB as shown in FIGS. 1A-1C uponadministration of a curcumin composition, a green tea extractcomposition, and a phycocyanin composition, as described herein,respectively. FIGS. 1A-1C show superior and unexpected NK3 inhibitionachieved by administration of various compounds, including a curcumincomposition (FIG. 1A), a green tea extract composition (FIG. 1B), and aphycocyanin composition (FIG. 1C), expressed as the IC50 (µg/mL), andwere 2.92 µg/ml, 16.9 µg/ml, and no IC50 value for the phycocyanincomposition was obtained, respectively.

Example 2 Method

In vivo experiments were performed to evaluate the efficacy of acurcumin composition, a green tea extract composition, a phycocyanincomposition, and the combination thereof as NK3 antagonists, bymeasuring hypothalamic levels of NKB.

Experimental Procedure

Female Wistar rats were purchased from Japan SLC Inc. (Shizuoka, Japan).At the age of 8 weeks, rate were ovariectomized or given a shamoperation (control) under isoflurane anesthesia. All animals wereindividually housed under clean conditions with controlled temperature,humidity, and light (12-hr light-dark cycle) and provided a standardcommercial diet and water ad libilum. All animal experimental procedureswere approved by the Institutional Animal Care and Use Committee ofTsukuba Research Center of Astellas Pharma Inc., which is accredited bythe Association for Assessment and Accreditation of Laboratory AnimalCare (AAALAC) International. Animals were handled and cared for inaccordance with the Guide for the Care and Use of Laboratory Animals.

Four weeks after surgery rats are randomly divided into 6 groups:sham-operated rats treated with a vehicle consisting of 0.5%methylcellulose solution (C); ovariectomized rats treated with a vehicleconsisting of 0.5% methylcellulose solution (OVX); and ovariectomizedrats treated with 600 mg HED of a curcumin composition, as describedherein (OVX+CL); 300 mg HED of a green tea extract composition, asdescribed herein (OVX+EGCG); 100 mg HED of a phycocyanin composition, asdescribed herein (OVX+P); and a combination composition, as describedherein, comprising 600 mg HED of a curcumin composition, as describedherein, 300 mg HED of a green tea extract composition, as describedherein, 100 mg HED of a phycocyanin composition, as described herein(OVX+CL+EGCG+P). Vehicles or active drugs were administered for 8 days.

Body weight and food intake were measured twice: before the firstadministration and on the final day of administration day. At day 5 ofrepeated administration, one small temperature data logger (ThermochronSL, KN Laboratories Inc., Osaka, Japan) was surgically implanted intothe abdominal cavity under isoflurane anesthesia and another wasattached to the skin of the tail using surgical tape and a handmadealuminum protector to prevent detachment. At day 7 of repeatedadministration, core, skin, and room temperatures were measured every 30min for 24 hr. Two to five hours after the final drug administration(10:00-14:00), blood samples were collected from the abdominal vena cavaunder isoflurane anesthesia and the uterus was isolated and weighed.Blood samples were centrifuged, and plasma was separated and stored at-80° C. until assay. Blood samples were analyzed for (i) serum levels ofglucose, triglycerides, cholesterol, aspartate aminotransferase (AST),alanine aminotransferase (ALT), urea, creatinine, malondialdehyde (MDA),antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT),and glutathione peroxidase (GSHPx), curcuminoids, EGCG, and phycocyaninextracts; (ii) calcium (Ca), inorganic phosphorus (P), and alkalinephosphatase (ALP); and (iii) plasma hormone levels such as estradiol,LH, FSH, progesterone and testosterone, according to known methods inthe art.

Brain tissue analysis was performed to evaluate levels of kisspeptin,NKB, GnRH, transient receptor potential cation channel subfamily Vmember 1 (TrpV1), and protein c-fos. Brain tissues were embedded inparaffin, and hypothalamic slices (3-µm thickness) containing the MnPOwere prepared according to a rat brain atlas (Paxinos and Watson, 2007)and standard procedures. After deparaffinization, the sections wereincubated with Immunosaver (Nisshin EM Co., Ltd., Tokyo, Japan) at 100°C. for 15 min for antigen retrieval followed by 3% hydrogen peroxide toblock endogenous per-oxidases. The samples were incubated with 1% bovineserum albumin for 20 min at room temperature followed by anti-kisspeptin, NKB, GnRH, TrpV1, or c-fos monoclonal antibody (dilution1:100) overnight at 4° C. The samples were then treated with the DAKOEnVision System (Agilent Technologies, Santa Clara, CA, USA). ImmPACTDAB (Vector Laboratories, Inc., Burlingame, CA, USA) was used for colordevelopment. The densitometric analysis of the relative intensityaccording to the control group of the western blot bands was performedwith β-actin normalization to ensure equal protein loading. Blots wererepeated at least three times (n = 3) and a representative blot isshown. ANOVA and Tukey’s post-hoc test were performed for statisticalcomparisons (p < 0.05). Data are presented as mean ± standard deviation.Different lowercase letters above data series (a-d) indicate astatistical difference between groups.

Quantitative assessment of c-Fos--positive neurons(stained-reddish-brown) was performed using a computerized imageanalysis system (WinROOF Ver. 6.0; Mitani Corp., Fukui, Japan) toautomatically (optimal color wavelength and approximate cell size wereentered in advance) count the number of reddish-brown (c-Fos-positive)cells in the MnPO under light microscopy at a magnification of 100x.

Results of hypothalamus levels of NKB following the treatment scheme ofExample 2 are shown in FIG. 2 . FIG. 2 shows superior and unexpectedresults. As expected, rats receiving the ovariectomy treatment (OVX),demonstrated the highest levels of NKB hypothalamus levels.Surprisingly, individual compositions according to the disclosure,significantly reduced NKB levels, below that of the OVX rats.Unexpectedly, a combination composition, as described herein(OVX+CL+EGCG+P), returned NKB levels to those seen in non-ovariectomizedmice receiving a saline treatment (C).

Example 3 Method

In vivo experiments were performed to evaluate the efficacy ofcombination compositions, of the disclosure, comprising a curcuminextract composition, a green tea extract composition, and a phycocyanincomposition of the disclosure, as NK3 antagonists, by measuringhypothalamic levels of NKB.

Experimental Procedure

The experimental procedure of Example 3 is the same procedure andanalysis as described in Example 2. In Example 3, various combinationcompositions, as disclosed herein, comprising varied amounts of acurcumin composition, a green tea extract composition, and a phycocyanincomposition according to the disclosure. In Example 3, the experimentalgroups were: sham-operated rats treated with a vehicle consisting of0.5% methylcellulose solution (C); ovariectomized rats treated with avehicle consisting of 0.5% methylcellulose solution (OVX);ovariectomized rats treated with 600 mg HED of a curcumin composition,300 mg HED of a green tea extract composition, 100 mg HED of aphycocyanin composition (OVX+CL1+EGCG1+P); 450 mg HED of a curcumincomposition, 450 mg HED of a green tea extract composition, 100 mg HEDof a phycocyanin composition (OVX+CL2+EGCG2+P); and 720 mg HED of acurcumin composition, 180 mg HED of a green tea extract composition, 100mg HED of a phycocyanin composition (OVX+CL3+EGCG3+P). Vehicles oractive drugs were administered for 8 days. Data are presented as mean ±standard deviation. Different lowercase letters above data series (a-d)indicate a statistical difference between groups.

Results of hypothalamus levels of NKB following the treatment scheme ofExample 2 are shown in FIG. 3 . FIG. 3 shows superior and unexpectedresults. As expected, rats receiving the ovariectomy treatment (OVX),demonstrated the highest levels of NKB hypothalamus levels.Surprisingly, all of the combination compositions evaluated,significantly reduced NKB levels, below that of the OVX rats.

1. A combination composition comprising an amount of a curcumincomposition, an amount of a green tea extract composition, and an amountof a phycocyanin composition.
 2. The combination composition of claim 1,wherein the amount of the curcumin composition, the amount of the greentea extract composition, and the amount of the phycocyanin compositioncomprise a synergistic ratio.
 3. The combination composition of claim 2,wherein the synergistic ratio is about 6:3:1, curcumin composition togreen tea extract composition to phycocyanin composition, respectively.4. The combination composition of claim 2, wherein the synergistic ratiois about 4.5:4.5:1, curcumin composition to green tea extractcomposition to phycocyanin composition, respectively.
 5. The combinationcomposition of claim 2, wherein the synergistic ratio is about7.2:1.8:1, curcumin composition to green tea extract composition tophycocyanin composition, respectively.
 6. The combination composition ofclaim 1, wherein the amount of the curcumin composition is about 100 mgto about 750 mg.
 7. The combination composition of claim 1, wherein theamount of the green tea extract composition is about 100 mg to about 500mg.
 8. The combination composition of claim 1, wherein the amount of thephycocyanin composition is about 100 mg.
 9. The combination compositionof claim 1, wherein when the combination composition is administered toa subject, the administration of the combination composition treats,ameliorates, prevents, or reduces symptoms associated with menopause inthe subject.
 10. The combination composition of claim 1, wherein thenthe combination composition is administered to a subject, theadministration of the combination composition treats, ameliorates,prevents, or reduces the effects of hot flashes, maintains a healthylevel of hot flashes in the subject, or both.
 11. The combinationcomposition of claim 1, wherein the combination composition isformulated as a dietary supplement or a pharmaceutical agent.
 12. Thecombination composition of claim 1, wherein the curcumin compositioncomprises a compound selected from the group consisting ofdiferuloylmethane, demethoxycurcumin, bis-demethoxycurcumin,tetrahydrocurcumin, dihydrocurcumin, hexahydrocurcumin,octohydrocurcumin, and any combination thereof.
 13. The combinationcomposition of claim 1, wherein the green tea extract comprises acompound selected from the group consisting of epigallocatechin gallate,epicatechin, epigallocatechin, and epicatechin gallate, and anycombination thereof.
 14. A method treating, ameliorating, preventing, orreducing symptoms associated with menopause in a subject, the methodcomprising: identifying that the subject is experiencing or willexperience symptoms associated with menopause; and administering acombination composition to the subject, wherein the combinationcomposition comprises a neurokinin 3 (NK3) antagonist.
 15. The method ofclaim 14, wherein the NK3 antagonist is selected from the groupconsisting of a curcumin composition, a green tea extract composition, aphycocyanin composition, and any combination thereof.
 16. The method ofclaim 15, wherein the combination composition comprises an amount of thecurcumin composition, an amount of the green tea extract composition,and an amount of the phycocyanin composition comprising a synergisticratio.
 17. The method of claim 16, wherein the amount of the curcumincomposition is about 100 mg to about 750 mg.
 18. The method of claim 16,wherein the amount of the green tea extract composition is about 100 mgto about 500 mg.
 19. The method of claim 16, wherein the amount of thephycocyanin composition is about 100 mg.
 20. A method treating,ameliorating, preventing, or reducing effects of hot flashes in asubject, the method comprising: identifying that the subject isexperiencing or will experience effects of hot flashes; andadministering a combination composition to the subject, wherein thecombination composition comprises a NK3 antagonist.
 21. The method ofclaim 20, wherein the NK3 antagonist is selected from the groupconsisting of a curcumin composition, a green tea extract composition, aphycocyanin composition, and any combination thereof.
 22. The method ofclaim 21, wherein the combination composition comprises an amount of thecurcumin composition, an amount of the green tea extract composition,and an amount of the phycocyanin composition comprising a synergisticratio.
 23. The method of claim 22, wherein the amount of the curcumincomposition is about 100 mg to about 750 mg.
 24. The method of claim 22,wherein the amount of the green tea extract composition is about 100 mgto about 500 mg.
 25. The method of claim 22, wherein the amount of thephycocyanin composition is about 100 mg.